Diabetes peripheral neuropathy (DPN) is, by far, the most prevalent microangiopathic complication of diabetes mellitus with a lifetime prevalence of around 50%.1 While it can manifest in several ways, including peripheral symmetric sensory-predominant neuropathy, autonomic neuropathy, focal/multifocal neuropathies, and motor neuropathy, painful diabetes peripheral neuropathy (DPNP) is, by far, the most distressing in terms of patient-led symptoms and poor quality of life by causing sleep disturbance, anxiety, and depression.2 Approximately 30–50% of subjects with DPN will have some symptoms of DPNP in their lifetime, often presenting as lancinating, stabbing, burning, electric shock-like sensations in a stocking and glove distribution. Pathophysiologically, it is a small-fiber neuropathy affecting the thinly myelinated Aδ and unmyelinated C nerve fibers causing peripheral neural hyperexcitability with further central sensitization.3 While risk factors for DPN, including dysglycemia, obesity, dyslipidemia, and smoking, are well established, specifically factors that modulate the development or worsening of DPNP are yet to be fully established.4

The management of DPNP has evolved over the years and broadly can be segregated into non-pharmacological (eg, transcutaneous electrical nerve and spinal cord stimulation) and pharmacological treatments. The latter comprises symptomatic analgesic agents acting either at the serotonin and norepinephrine-mediated descending inhibitory nociceptive pathways (duloxetine, amitriptyline), the α2δ subunit of calcium voltage-gated channels depressing dorsal horn sensitivity (gabapentin, pregabalin) or disease-modifying therapies like antioxidants (alpha-lipoic acid, benfotiamine) and topical capsaicin.5 Most international pain guidelines recommend duloxetine, amitriptyline, pregabalin, or gabapentin as first-line agents for symptomatic DPNP. In addition, the US Food and Drug Administration (FDA) and the European Medicines Agency have approved the 8% capsaicin patch.6 7

Despite the evolution of new molecules and mechanisms, the management of DPNP over the years has remained subtherapeutic due to a multitude of reasons. First, monotherapy using any of the above first-line pharmacological agents at best is ~50% effective in the majority of patients, and attempts to increase efficacy are frequently accompanied by dose-limiting side effects. Furthermore, while there is evidence for individual efficacy for each drug, there is an absence of any robust head-to-head comparison except for a couple of studies, including the COMBO-DN study,8 making it hard to select a particular agent. Second, since pain relief of DPNP is not sufficient in monotherapy or offset with side effects, combination or sequential therapy is frequently attempted. The evidence base for combination treatment is again thin, and the recent OPTION-DM study showed that various combination treatments did not have superiority against each other, and pain relief with combination treatments was still suboptimal.9 Finally, while the above-named agents are predominantly aimed at improving symptomatic analgesia, there has been a dearth of disease-modifying agents which work against pain pathophysiology. Both alpha-lipoic acid and benfotiamine (licensed in Europe but not FDA approved) are purported to reduce endoneurial hypoxia and nerve dysfunction by reducing free radical formation but do not have large-scale randomized trials to show long-term efficacy.

Topical capsaicin is an alkaloid extracted from red chili peppers and acts as a selective agonist for transient receptor potential vanilloid 1 (TRPV1) receptors located mainly in the nociceptive neurons of the peripheral nervous system, but they have also been described in many other tissues, including the central nervous system. TRPV1 is involved in the transmission and modulation of pain as well as the integration of diverse painful stimuli, which are upregulated and hyperactive in various neuropathic pain conditions including DPNP. Binding of capsaicin to the TRPV1 receptors leads to neurolysis of TRPV1-expressing nociceptors.10 However, repeated applications are necessary due to regrowth of neural fibers. Initial studies using topical capsaicin formulations in the form of 0.025% capsaicin gel or 0.075% capsaicin lotion were not found to be superior to placebo in relieving DPNP.11 However, Simpson et al in a randomized, double-blind, placebo-controlled study involving 369 subjects showed that with a single application of 8% capsaicin patch for 30 min, the decrease in average daily pain scores from baseline to weeks 2–8 was significantly higher for the capsaicin patch than placebo (–27.4% vs –20.9%, p=0.025).12

The CASPAR study by Überall et al is a retrospective, real-world, non-interventional multicohort study to evaluate the 8% capsaicin topical system for treating DPNP.13 It uses online patient-reported pain data between 2015 and 2021 based on validated pain questionnaires. Being a real-world study, it is open labeled, independent, physician led, and subjects received a variable number of repeat topical treatments at three monthly intervals based on individual requirements and decisions made by their treating physicians. It would be important to specify that this is specifically a pain response outcome study and was not designed to take into account the etiopathogenetic factors like glycemic control, dyslipidemia status, etc, nor to look at outcomes like small and large objective neural outcomes (eg, skin biopsy or nerve conduction studies).

The study attempts to answer some important questions related to the efficacy of the 8% topical capsaicin patch. First, it assesses the improvement of various aspects of the pain syndrome, including pain intensity, severity and phenotype. Second, it also evaluates the efficacy of the medication in pain-related psychosocial aspects including impairments of daily activities, quality of life, mental well-being and depression. Third, and importantly, it examines the ability of this drug to reduce the usage of concomitant analgesic medications including opioids and consequently the side effects of these drugs. Finally, since topical capsaicin is associated with cutaneous side effects like burning and erythema, it addresses the treatment discontinuation rates after single or multiple applications.

While a detailed outcome analysis is available in the manuscript, the study shows a consistent pain score reduction with even one application (p<0.001 vs baseline), and improvement increases with further applications (≥30% decrease in 24-hour average pain intensity scores from baseline—58.3%, 98.1%, 100%, and 100% after the first, second, third, and fourth applications, respectively). Other pain improvements were on similar lines and improved with each further application. Furthermore, this study has been successful in addressing another important unmet need in the current management of DPNP, that is, use of concomitant pain medications. Use of four applications of 8% capsaicin in addition to existing drugs and in any combination demonstrated a significant reduction in mean concomitant pain medications from 4.1 at baseline to 1.2 at 12 months (p<0.001). A similarly impressive outcome was that the proportion of patients not taking any concomitant pain medications increased with ongoing treatments, with approximately one-third of patients who received at least three treatments being able to discontinue all concomitant pain medications by 12 months. This suggests that 8% capsaicin has both a synergistic and a drug-sparing advantage in the management of DPNP.

While a more diverse population study group would have further enriched the applicability of the data to other geographical areas, there is no doubt that the findings of the CASPAR study would be beneficial to most physicians managing patients with DPNP and allow further flexibility in drug regimens to manage both pain symptoms as well as side effects.